Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II - induced cardiac hypertrophy and vascular remodeling

2021 ◽  
Author(s):  
Irakli Kopaliani ◽  
Natalia Jarzebska ◽  
Silke Brilloff ◽  
Anne Kolouschek ◽  
Jens Martens-Lobenhoffer ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Vascular Remodeling ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
High Dose ◽  
Dimethylarginine Dimethylaminohydrolase ◽  
Cross Sectional ◽  
Cardiovascular Remodeling

Background: Cardiovascular complications are the leading cause of death and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of DDAH1 (dimethylarginine dimethylaminohydrolase 1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from Ang II-induced end organ damage. Methods and Results: Angiotensin II (ANGII) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (TG) and wild type (WT) littermates for two or four weeks. Echocardiography was performed in the first and fourth week of the infusion, systolic blood pressure (SBP) was measured weekly and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after one week of ANGII infusion was not different between the groups, while TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 weeks of ANGII infusion in the high dose and after 4 weeks in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross sectional area and less interstitial fibrosis as compared to WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2 and showed better endothelium-dependent relaxation. Conclusions: We demonstrated that overexpression of DDAH1 protects from ANGII-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.

Abstract 382: Transgenic Overexpression of Dimethylarginine Dimethylaminohydrolase 1 Protects From Angiotensin II-induced Cardiac Hypertrophy

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Roman N Rodionov ◽  
Silke Brilloff ◽  
Natalia Jarzebska ◽  
Anne Kolouschek ◽  
Jens Martens-Lobenhoffer ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Posterior Wall ◽  
Organ Damage ◽  
Left Ventricular ◽  
Wild Type ◽  
Dimethylarginine Dimethylaminohydrolase ◽  
Posterior Wall Thickness

Background: ADMA (asymmetric dimethylarginine) is an endogenous inhibitor of nitric oxide synthase. ADMA can be metabolized to citrulline by dimethylarginine dimethylaminohydrolase (DDAH). DDAH1 overexpression lowers ADMA and protects from angiotensin II - induced renal interstitial fibrosis and vascular oxidative stress. The goal of the current study was to test the hypothesis that transgenic overexpression of DDAH1 protects from angiotensin II-induced cardiac hypertrophy. Methods and Results: DDAH1 transgenic mice grew and developed normally and had decreased plasma ADMA levels. Angiotensin II was infused for four weeks in the dose of 0.75 mg/kg/day in DDAH1 transgenic mice and wild type littermates via osmotic minipumps. Echocardiography was performed in the first and fourth week after start of the infusion on anaesthetized mice. After 4 weeks of angiotensin II infusion wild type mice developed cardiac hypertrophy. The DDAH1 transgenic mice had higher left ventricular lumen to wall ratio compared to the wild type mice (1.76 ± 0.18 vs 1.15 ± 0.22, P<0.01). They also had lower left ventricular posterior wall thickness in systole and diastole as compared to the wild type controls (1.18 ± 0.03 mm vs 1.95 ± 0.16 mm, P<0.001 and 0.81 ± 0.03 mm vs 1.62 ± 0.25 mm, P<0.001, respectively). Conclusion: We demonstrated that upregulation of DDAH1 protects from angiotensin II-induced cardiac hypertrophy. Our findings suggest that ADMA plays a role in angiotensin II - induced myocardial remodeling. Upregulation of DDAH1 might be a potential approach for protection from angiotensin II - induced end organ damage.

scholarly journals NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload

2019 ◽  
Author(s):  
Moritz Schnelle ◽  
Iain Sawyer ◽  
Narayana Anilkumar ◽  
Belal A Mohamed ◽  
Daniel A Richards ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Volume Overload ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiac Cells ◽  
Cross Sectional ◽  
Nadph Oxidase 4

Abstract Aims Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling. Methods and results We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4−/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4−/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P &lt; 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P &lt; 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs. 379 μm2, P &lt; 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4−/− mice (+29% vs. −21%, P &lt; 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4−/− mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A. Conclusion Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

2006 ◽  
Vol 290 (6) ◽  
pp. H2522-H2527 ◽  
Author(s):  
Hideaki Morita ◽  
Sanjaya Khanal ◽  
Sharad Rastogi ◽  
George Suzuki ◽  
Makoto Imai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
High Dose ◽  
Long Term Effects ◽  
Cross Sectional ◽  
Mmp Inhibitor ◽  
Lv Dysfunction

Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), ≤36%] was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 mo of therapy with either high-dose (HD) PG (3.5 mg/kg, n = 8), low-dose (LD) PG (0.2 mg/kg, n = 8), or to a matched placebo (PL, n = 8). PG has been shown to produce complete inhibition of MMP-2, -3, -9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 mo after initiating therapy. In PL and LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-mo follow-up period. Whereas in HD dogs ejection fraction increased from 36 ± 1 to 40 ± 1% ( P = 0.003), EDV and ESV decreased (59 ± 4 vs. 57 ± 4 ml, P = 0.02; and 38 ± 2 vs. 34 ± 2 ml, P = 0.00001, respectively). When compared with controls, HD-treated dogs showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis, and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD- but not LD-treated dogs. In conclusion, in dogs with moderate HF, long-term monotherapy with HD selective MMP inhibitor PG prevents LV remodeling and the progression of global LV dysfunction.

scholarly journals Chronic C-Type Natriuretic Peptide Infusion Attenuates Angiotensin II-Induced Myocardial Superoxide Production and Cardiac Remodeling

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yasuhiro Izumiya ◽  
Satoshi Araki ◽  
Hiroki Usuku ◽  
Taku Rokutanda ◽  
Shinsuke Hanatani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Superoxide Production ◽  
Heart Weight ◽  
Ang Ii ◽  
Myocardial Oxidative Stress

Myocardial oxidative stress and inflammation are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived cardioprotective factor, although its effect on cardiac superoxide generation has not been investigated in vivo. This study tested the hypothesis that suppression of superoxide production contributes to the cardioprotective action of CNP. Angiotensin II (Ang II) or saline was continuously infused subcutaneously into mice using an osmotic minipump. Simultaneously with the initiation of Ang II treatment, mice were infused with CNP (0.05 μg/kg/min) or vehicle for 2 weeks. The heart weight to tibial length ratio was significantly increased by Ang II in vehicle-treated mice. Treatment with CNP decreased Ang II-induced cardiac hypertrophy without affecting systolic blood pressure. Echocardiography showed that CNP attenuated Ang II-induced increase in wall thickness, left ventricular dilatation, and decrease in fractional shortening. CNP reduced Ang II-induced increases in cardiomyocyte size and interstitial fibrosis and suppressed hypertrophic- and fibrosis-related gene expression. Finally, CNP decreased Ang II-induced cardiac superoxide production. These changes were accompanied by suppression of NOX4 gene expression. Our data indicate that treatment with CNP attenuated Ang II-induced cardiac hypertrophy, fibrosis, and contractile dysfunction which were accompanied by reduced cardiac superoxide production.

scholarly journals Hesperidin Prevents Nitric Oxide Deficiency-Induced Cardiovascular Remodeling in Rats via Suppressing TGF-β1 and MMPs Protein Expression

2018 ◽  
Author(s):  
Putcharawipa Maneesai ◽  
Sarawoot Bunbupha ◽  
Prapassorn Potue ◽  
Thewarid Berkban ◽  
Upa Kukongviriyapan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis Factor ◽  
Matrix Metalloproteinase ◽  
Protein Expression ◽  
Wall Thickness ◽  
Tumor Necrosis ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Cardiovascular Remodeling ◽  
Necrosis Factor

Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by N-nitro L-arginine methyl ester (L-NAME) in rats.&nbsp; Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg); L-NAME plus hesperidin (15 mg/kg), or hesperidin (30 mg/kg), or captopril (2.5 mg/kg) for five weeks (n = 8/group). Hesperidin or captopril significantly prevented the development of hypertension in L-NAME rats.&nbsp; Moreover, hesperidin or captopril alleviated L-NAME-induced cardiac remodeling; increases in wall thickness, cross sectional area (CSA) and fibrosis of left ventricular (LV), and vascular remodeling; increases in wall thickness, CSA, vascular smooth muscle cells and collagen deposition in the aorta. These were associated with reduced oxidative stress markers, tumor necrosis factor-alpha (TNF-&alpha;), transforming growth factor-beta 1 (TGF-&beta;1) and enhancing plasma nitric oxide metabolite (NOx) in L-NAME treated groups. Furthermore, up-regulation of tumor necrosis factor receptor type 1 (TNF-R1) and TGF-&beta;1 protein expression and the over-expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) were suppressed in L-NAME rats treated with hesperidin or captopril. These data suggested that hesperidin had cardioprotective effects in L-NAME hypertensive rats. The possible mechanism may involve its antioxidant and anti-inflammatory effects.

scholarly journals Leonurine Attenuates Pressure-Overload Cardiac Hypertrophy Induced By Abdominal Aortic Constriction In Rats

2021 ◽  
Author(s):  
Ding Xiaoli ◽  
Yuan Qingqing ◽  
Qian Haibing
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Ang Ii ◽  
Aortic Constriction ◽  
Qrt Pcr ◽  
Abdominal Aortic

Abstract Background: Myocardial hypertrophy occurs in many cardiovascular diseases. Leonurine (Leo) is commonly used for cardiovascular and cerebrovascular diseases. However, whether it can prevent cardiac hypertrophy is not known. The aim of this study was to investigate the effect and mechanism of Leonurine (Leo) against pressure-overload cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Methods: To answer this question, we prove it in the following way: Cardiac function was evaluated by hemodynamic; the left ventricle enlargement was measured by heart weight index (HWI) and left ventricular mass index (LVWI); myocardial tissue changes and myocardial cell diameter (MD) were determined by Hematoxylin and eosin (HE) staining; theβ-myosin heavy chain(β-MHC)and atrial natriuretic factor (ANF), which are recognized as a marker of cardiac hypertrophy, were determined by Real-time quantitative PCR (qRT-PCR), then another gene phospholipase C (PLC), inositol triphosphate (IP3), which associated with RAS were determined by Western blot(WB). angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R) were determined by ELISA, WB and qRT-PCR methods. Finally, we measured the level of Ca2+ by microplate method and the protooncogene c-fos and c-myc mRNA in left ventricular myocardium by qRT-PCR.Results: Compare with control group, Leonurine can improve systolic dysfunction; inhibit the increase of left cardiac; inhibit myocardial cells were abnormally large and restrain the changes of cardiac histopathology; decrease the expression of β-MHC, ANF, Ang II, AT1R, c-fos and c-myc mRNA and the protein levels of PLC, IP3, AngII and AT1R in left ventricular myocardium, in addition, the content of Ca2+ also decrease. Conclusion: Therefore, Leonurine can inhibit cardiac hypertrophy induced by AAC and its effects may be associated with RAS.

Abstract 478: FGF23 Expression in Cardiac Fibroblasts Is Augmented by S100/Calgranulins-Mediated Inflammation and Associated With Cardiac Hypertrophy, but Not in Angiotensin II-Induced Cardiac Hypertrophy

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Marion Hofmann Bowman ◽  
Brandon Gardner ◽  
Judy Earley ◽  
Debra L Rateri ◽  
Alan Daugherty ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Heart Weight ◽  
Ang Ii ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Transgenic Expression ◽  
Significant Difference

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p<0.04), decreased E/A ratio, and increased LVPW thickness, and associated with increased expression of FGF23 mRNA and protein in cardiac tissue lysates (2-4 fold increase). Similarly, Ang II induced significant LVH compared to saline infused LDLR-/- mice (6.1±1.3 vs. 3.6 ±0.9 mg/g, p<0.01), and associated with increased mRNA for hypertrophic genes (ANP, BNP, b-MHC, CTGF and Col1a1). However, there was no significant difference in FGF23 mRNA and protein between Ang II and saline infused mice. Cardiac hypertrophy was attenuated in AngII-infused mice with deficiency of AT1aR (S100A4-Cre+/-xAT1aRxLDLR-/-). In vitro, Ang II (100nM) did not induce FGF23 in valvular interstitial fibroblasts or myocytes. Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.

Abstract 152: Mitochondrial Fission Inhibitor Mdivi-1 Attenuates Angiotensin II-Induced Cardiovascular Remodeling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Steven J Forrester ◽  
Tatsuo Kawai ◽  
Katherine J Elliott ◽  
Kunie Eguchi ◽  
Victor Rizzo ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Er Stress ◽  
Mitochondrial Fission ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiovascular Remodeling ◽  
Target Organs ◽  
Quantity Control ◽  
Affect Heart Rate

Mitochondrial dysfunction has been implicated in various types of cardiovascular diseases which may involve overload and de-compensation in mitochondrial quality/quantity control. However, limited mechanistic insight is available regarding the contribution and mechanism of mitochondrial quality control in hypertension. In the present study, we tested our hypothesis that enhancement of mitochondrial fission in vascular cells is involved in hypertensive vascular remodeling. 8 week old male C57/Bl6 mice were infused with angiotensin II (1000 ng/kg/min) for 2 weeks with or without treatment of mitochondrial fission inhibitor Mdivi-1 (25 mg/kg ip every other day). Mdivi-1 significantly inhibited AngII-induced left ventricular hypertrophy assessed by heart weight body weight ratio as well as by echocardiogram. Histological assessment of the Mdivi-1-treated mouse hearts further demonstrated significant suppression of vessel hypertrophy and fibrosis induced by AngII. However, Mdivi-1 did not affect heart rate or hypertension induced by AngII assessed by telemetry. KDEL and VCAM1 staining of the heart and aorta suggest attenuation of vascular ER stress and inflammation, respectively. In cultured rat vascular smooth muscle cell (VSMCs), AngII induced mitochondrial fission promoting Drp1 phosphorylation at Ser616 and Ser637. Pretreatment of Mdivi-1 (5 microM 30 min) attenuated 100 nM AngII-induced mitochondrial fission in VSMCs assessed by mito-tracker staining. Mdivi-1 also attenuated extracellular collagen accumulation induced by AngII in VSMCs assessed by Sirius Red staining quantification kit. In conclusion, this data suggests that Mdivi-1 treatment prevents AngII-induced cardiovascular remodeling independently of hypertension via suppression of mitochondrial fission and attenuation of ER stress and inflammation in target organs.

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